T regulatory cells (Treg) or suppressor T cells are functionally defined as T cells that inhibit the immune response by influencing the activity of another cell. These cells comprise a small population of thymus derived CD4+ T cells. Despite there small population, these T regulatory cells have a large regulatory effect on the immune system. Overactivity of these T regulatory cells can contribute to the resistance of tumors and infections to the immune system, where this resistance may take the form of, e.g., tolerance to the tumor, progressing lesions in cancer, and persistent bacterial and viral infections, see, e.g., Shimizu, et al. (2002) Nat. Immunol. 3:135-142; Shimizu, et al. (1999) J. Immunol. 163:5211-5218; Antony and Restifo (2002) J. Immunotherapy 25:202-206; McGuirk and Mills (2002) Trends Immunol. 23:450-455; Tatsumi, et al. (2002) J. Exp. Med. 196:619-628; Jonuleit, et al. (2001) Trends Immunol. 22:394-400.
Additionally, T regulatory cells mediate inflammatory and autoimmune disorders. For example, CD25+CD4+ T regulatory cells play a role in preventing, e.g., autoimmune gastritis, thyroiditis, insulin-dependent diabetes melitus (IDDM), inflammatory bowel disorders (IBD), experimental autoimmune encephalomyelitis (EAE), food allergies, and graft rejection. Conversely, impaired T regulatory cell activity can promote autoimmune disorders, see, e.g., Wing, et al. (2003) Eur. J. Immunol. 33:579-587; Sakaguchi, et al. (2001) Immunol. Revs. 182:18-32; Suri-Payer, et al. (1998) J. Immunol. 160:1212-1218; Shevach (2001) J. Exp. Med. 193:F41-F45; Read and Powrie (2001) Curr. Op. Immunol. 13:644-649.
To function properly, the immune system must discriminate between self and non-self. When self/non-self discrimination fails the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases. Regulatory T cells actively suppress activation of the immune system and prevent pathological self-reactivity, i.e. autoimmune disease. The critical role regulatory T cells play within the immune system is evidenced by the severe autoimmune syndrome that results from a genetic deficiency in regulatory T cells.
Moreover, large numbers of these regulatory cells have been found in cancerous tissue. The presence of regulatory T cells at the site of a tumor results in the creation of a favorable environment for tumor growth. Ideally, the presence and action of T regulatory cells at the site of tumor growth would be reduced so that an immune response could be mounted to the growing tumor.
The molecular mechanism by which regulatory T cells exert their suppressor/regulatory activity has not been definitively characterized and is the subject of intense research. In vitro experiments suggest that suppressive mechanism requires cell-to-cell contact with the cell being suppressed. However, the immunosuppressive cytokines TGF-beta and interleukin-10 (IL-10) have also been implicated in regulatory T cell function.
Despite numerous attempts and reports, immunotherapeutic intervention does not often generate long lasting effector T cell responses and therapeutic immunity. T regulatory (Treg) cells play a central role in regulation of self-tolerance and control of responses to alloantigens. They comprise 5-10% of all CD4+ T cells, constitutively express the CD25 and CTLA-4 markers and suppress the activation of effector CD4+ and CD8+ cells and even dendritic cells. They have been implicated in wide variety of immunosuppressive responses, such as maternal tolerance to the fetus, autoimmunity and tumor survival. Dysfunction or depletion of Treg cells lead to spontaneous onset of various immune or autoimmune disorders, such as organ-specific autoimmune diseases in mice or nickel-allergic responses in humans. As recently reported, two subsets of Treg cells, natural and adaptive, differ in terms of specificity and effector mechanisms (Bluestone et al. (2003) Nat Rev Immunol. 3:253-7). While the natural Treg cell subset develops in the thymus to prevent potentially pathological autoimmune reactions, the adaptive Treg cells develop as result of activation of mature T cells under particular conditions of sub-optimal antigen exposure and co-stimulation (Bluestone et al. supra). Treg-mediated suppressive activity has been shown to be both cell-cell contact independent and dependent. For example, antigen-specific tumor infiltrating human CD4+CD25+ Treg cells requires cell contact and ligand-specific activation (via LAGE protein). Treg cells migration, particularly skin-homing, is controlled by chemokines, which signal via binding to differentially expressed chemokine receptors, namely CCR4 and CCR8 (thus, these cells are attracted to MDC/CCL22, TARC/CCL17, I-309/CCL1 or viral chemokine vMIP-I and vMIP-III (lellem et al. (2001) J Exp Med. 194:847-53). Chemokine receptors are also differentially expressed on various immune cells. For example, cutaneous T cell lymphoma and adult T-cell leukemia/lymphoma (ATLL) cells over express CCR4, which was recently associated with unfavorable outcome of the disease (Ishida et al. (2003) Clin Cancer Res. 9:3625-34). In fact, expression of CCR4 was also associated with skin homing of Tregs and the infiltration of Tregs at tumor site, including B cell malignancies which produce CCL2 (Scrivner et al. (2003) Leuk Lymphoma. 44:383-9).
Due to the involvement of T regulatory cells in the progression of many diseases and disorders, the need exists to be able to modulate the activity of these T cells and, ultimately, the entire immune system, for the treatment of these diseases and disorders.